Mechanisms of Sickness, Fatigue and Depression

Tissue damage induced by cancer treatment or the tumor itself can lead to peripheral inflammation that may propagate to the central nervous system. Activation of immune-to-brain communication pathways accounts for why we feel sick and behave in a sick way when we are ill. Sickness is a normal adaptive response in the face of an infection or tissue damage, and it helps the individual to cope with their dangers.

This adaptive response can become awry when the “danger” represented by cancer therapy occurs repeatedly or when the central nervous system is already fragile, such as during aging. Cancer patients then experience exacerbated symptoms that can persist during survivorship after cessation of cancer therapy.

Current Symptom Studies

We are studying how a regimen of chemotherapy and radiotherapy that helps the organism to clear the tumor can induce behavioral alterations, using a murine model of human papilloma virus-related oropharynx squamous cell carcinoma. We are testing the hypothesis that tumor growth is associated with behavioral alterations that are mediated by the propagation of inflammation from the tumor to the liver and brain. We are also investigating whether exosomes released by tumor cells contribute to this propagation of inflammation.

Our studies of the neurotoxicities associated with cancer therapy focus on mitochondrial dysfunction and on possible alterations in molecules that affect the immune system and that include danger signals, such as inflammatory and anti-inflammatory cytokines and the tryptophan-degrading enzyme indoleamine 2, 3 dioxygenase (IDO). Immune-mediated activation of IDO contributes to immunotolerance of tumor cells but also favors the generation of neurotoxic kynurenine metabolites in the brain.

References

Fatigue is the most common symptom experienced by cancer patients and it can be profoundly debilitating. Because the feeling of fatigue is very complex, we have chosen to assess specific components of this feeling, including the lack of motivation and the decreased ability to engage in goal-directed behavior. This is done using computerized tasks that have behavioral equivalents in animal models of fatigue, therefore allowing study of underlying mechanisms, including the role of the tryptophan-degrading enzyme indoleamine 2, 3 dioxygenase.

References

Activation of the immune system is associated with an increased risk for depression that is mediated by enhanced activity of the tryptophan-degrading enzyme indoleamine 2, 3 dioxygenase. This enzyme is responsible for an increase in kynurenine, a metabolite of tryptophan. Kynurenine needs to be transported across the blood-brain barrier to be metabolized further into kynurenine metabolites that are neurotoxic. We are searching for ways to interfere with the transport mechanisms that are responsible for the entry of kynurenine into the brain.